title: Screening-based discovery of the first novel ATP competitive inhibitors of the Staphylococcus aureus essential enzyme UMP kinase.
abstract: UMP kinase (PyrH) is an essential enzyme found only in bacteria, making it ideal as a target for the discovery of antibacterials. To identify inhibitors of PyrH, an assay employing Staphylococcus aureus PyrH coupled to pyruvate kinase/lactate dehydrogenase was developed and was used to perform a high throughput screen. A validated aminopyrimidine series was identified from screening. Kinetic characterization of this aminopyrimidine indicated it was a competitive inhibitor of ATP. We have shown that HTS can be used to identify potential leads for this novel target, the first ATP competitive inhibitor of PyrH reported.
authors.affiliation: Discovery Sciences, AstraZeneca R&D Boston, Waltham, MA 02451, United States. Peter.Doig@AstraZeneca.com
authors.forename: Peter
authors.initials: P
authors.lastname: Doig
authors.forename: Elise
authors.initials: E
authors.lastname: Gorseth
authors.forename: Tory
authors.initials: T
authors.lastname: Nash
authors.forename: Arthur
authors.initials: A
authors.lastname: Patten
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
authors.forename: Carolyn
authors.initials: C
authors.lastname: Blackett
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D057075:Enzyme Assays; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D015203:Reproducibility of Results; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; D000255:Adenosine Triphosphate; C023276:uridine monophosphate kinase; D009703:Nucleoside-Phosphate Kinase; C030986:pyrimidine
keywords: Antibacterial targets; HTS; Inhibitor; PyrH; Screening; UMP kinase